The present invention relates to neurotropic peptides which effect increased turnover and release of the catecholamine dopamine, thereby regulating the release of gonadotropins and prolactin by the pituitary gland in mammals.
Peptides are compounds which contain two or more amino acids in which the carboxyl group of one acid is linked in peptide bond to the amino group of the other acid. Conventional representations of peptides are constructed such that the amino group appears to the left and the carboxyl group to the right; the position of the amino acid residues, usually identified by trivial names, are numbered from left to right as indicated in the example of a tripeptide below where R=the ionizing group of a specific amino acid ##STR1##
The pituitary gland is attached by a stalk to the region in the base of the brain known as the hypothalamus. The anterior portion of the pituitary secretes a number of protein hormones that travel through the bloodstream to reach other organs of internal secretion. In particular, the reproductive hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH), collectively called gonadotropins, as well as prolactin (PRL), are released by the pituitary gland and stimulate the production of gametes and steroid hormones by the gonads.
Pituitary gonadotropins and prolactin are necessary for reproduction, and their secretion requires prior synthesis and release of hypothalamic factors such as gonadotropin hormone releasing hormone (GnRH) and catecholamines. The catecholamine norepinephrine (NE) stimulates GnRH release from the hypothalamus; in contrast, a second catecholamine dopamine (DA) generally inhibits GnRH release consequently reducing gonadotropin, prolactin and gonadal steroid secretion. In mammals, hypothalamic control of reproduction is modulated by yet another part of the brain, the epiphysis cerebri or pineal gland, which plays primarily an inhibitory or antigonadotropic role in several species.
Since the first reports of abnormal reproductive development in humans with pineal gland tumors (Huebner, O., Tsch. Med. Wschr. 24:214-222, 1898; Kitay, J. I. and M. D. Altschule, The Pineal Gland, Cambridge:Harvard Press, 1954), questions have been posed about the chemical nature of pineal hormones and particularly about the nature of the hormonal mediators of pineal antigonadotropic function. It is clear from modern investigations that the pineal gland regulates reproduction in most mammals through modulation of the hypothalamic-pituitary-gonadal axis in response to a number of environmental factors.
The pineal hormonal factors mediating this function vary among species. For example, in the hamster and sheep, indolic compounds derived from serotonin may convey the pineal's hormonal message to the hypothalamus, whereas this is not the case in the more commonly employed laboratory rat. Early work in this area suggested that in the human, rat and mouse the pineal antigonadotropic factor is proteinaceous in character (for review see: Benson, B. and I. Ebels, In: The Pineal Gland, Ed. by R. J. Reiter, CRC Press, Boca Raton, pp.165-187, 1981); more recent investigations suggest that this antigonadotropin acts by stimulation of hypothalamic dopamine synthesis (Benson, B. et al., in: Role of Peptides and Proteins in Control of Reproduction, Ed. by S. M. McCann and D. S. Dhindsa, Elsevier Sci. Pub. Co., N. Holland, pp. 111-130, 1933; Benson, B. et al., in: Advances In Pineal Research, Vol. 4, Ed. by R. J. Reiter and A. Lukaszyk, Libbey & Co., Ltd., pp. 99-111, 1990).
For many years investigators have searched for potent antagonists of GnRH, the hypothalamic decapeptide that regulates pituitary secretion of gonadotropins (M. Karten and Je. E. Rivier, Endocrine Reviews 7:44-66, 1986). The high degree of interest in such antagonists is due to their usefulness in the fields of reproductive endocrinology, gynecology, contraception and oncology. In general most prior art GnRH antagonists are GnRH analogs in which the GnRH amino acid sequence has been modified by the deletion and/or replacement of key amino acids, particularly those at positions 2 or 6. See, for example, the United States patents listed below.
______________________________________ U.S. PAT. NO. INVENTOR ISSUE DATE ______________________________________ 3,933,782 Yardley 01/20/76 3,941,763 Sarantakis 03/02/76 4,253,997 Sarantakis 03/03/81 4,307,083 Rivier et al. 12/22/81 4,619,914 Vale et al. 10/28/86 4,800,191 Schally et al. 01/24/89 4,801,577 Nestor et al. 01/31/89 4,866,160 Coy et al. 09/12/89 ______________________________________
The desired GnRH analogs are those that bind to the GnRH receptor and block endogenous GnRH access to the receptor, thus rendering endogenous GnRH ineffective.
In contrast to the prior art GnRH antogonists, the pineal antigonadotropin of the present invention effects GnRH antagonism via a different mechanism, viz. by inhibition the release of GnRH from the hypothalamus. The distinction between the prior art and the present invention is illustrated in FIG. 1, which is a diagram of the hormonal control of reproduction. Because the inhibition is accomplished by increased turnover and release of catecholamines including the potent prolactin inhibiting factor dopamine, pituitary prolactin secretion is concomitantly reduced by the pineal antigonadotropin. The potential utility of the pineal antigonadotropic peptide of the present invention extends therefore beyond the uses in reproductive endocrinology mentioned above to other areas of neuroscience, including neuropathological states such as Parkinson's and Alzheimer' disease which may be caused by deficits in catecholaminergic neurotransmitters.